2-methyl-17alpha-ethynyl-delta1, 4-androstadiene-11beta, 17beta-diol-3-one and proces its preparation



United States Patent Ofihce 3,658,252 Patented Dec. 11, 1952 3,068,252Z-METHYL-Uu-ETHYNYL n -ANDRflfiTADiENE- 115,17fi-DIOL-3-0NE AND PROQESSFUR HTS PREPARATEON Gerard Nomine, Noisy-le-Sec, Daniei Eertin,Montrouge, and Hubert Fritel, Paris, France, assignors, by mesneassignments, to RoussehUJLAlF, A., Paris, France, a corporation ofFrance N0 Drawing. Filed Oct. 25, 1960, Ser. No. 64,73 Claims priority,application France Nov. 2t 1959 1 Claim. (Ci. zen-397.45

antilipemic activity.

It is another object of the invention to produce 2 methyl 17oz ethynyl-A-androstadiene11e,17[3diol- 3-one from IIB-hydroxy-testosterone by anovel process.

It is a further object of the invention to obtain as novel intermediatesfor Z-methyl-l7a-ethynylA -androstadiene- 11,8,17e-diol-3-one thefollowing compounds:

(a) 2-ethoxalyl-M-androstene-116,17B-diol-3-one (II) (b)2-methyl-Z-ethoxalyl-A -androstene 115,175 diol- 3-one (II!) (c)Za-methyl-M-androstene-11B,17B-diol-3-one (IV) (d) The 17-acetate of2ot-methyl-A -androstene-115,175-

diol-3-one (V) (e) The 17-acetate of 2 methyl A androstadiene-11B,l7,8-diol-3-one (VI) (7) 2-methyl-A-androstadiene-11B,17,8-diol-3-one (Vii) (g) 2-methy1-A-androstadiene-11 8-ol-3,17-dione (VIII) These and other objects andadvantages of the invention will become more obvious from the followingdetailed description.

According to the process of the invention, Z-methyl- 17a-ethyny1-Aandrostadiene-115,17B-diol-3-one is produced by starting withllfi-hydroxy testosterone which may be obtained by the technique of Herret a1. [1. Am. Chem. Soc., vol. 75 (1953), p. 5927]. The llfi-hydroxytestosterone is ethoxalylated in the 2-position in the presence of analkaline agent to form 2-ethoxalyl-A -androstene-l15,17fi-diol-3-one,the latter is treated with methyl halide in an alkaline medium to form2-methyl-2-ethoxalyl-M-androstene-l1,3,175-dio1-3-one, the said productis deacylated to form 2a-methyl-A -androstene-115,17p-diol- 3-one, thelatter is acetylated to form the 17-acetate ofZa-methyl-M-androstene-1lfi,l7[3-diol-3-one, the said 17- acetate isthen dehydrogenated to form the 17-acetate of 2-methyl-A-androstadiene-115,17fi-dio1-3-one, the latter 17-acetate is saponifiedunder alkaline conditions to the free 2-methyl-A-androstadiene-115,17fi-diol-3-one which is then treated by theOppenauer method with an aluminum lower alkanolate in an organic solventto form 2- methyl-A -androstadiene-llfi-ol-3,l7-dione. The lattercompound is then reacted with acetylene to form the desiredZ-methyl-lh-ethynyl A androstadiene-11fi,175- diol-3-one. Table I showsthe reaction scheme of the present invention.

TABLE I HO on vxrr HO oa "nzcu A preferred mode of the inventionconsists of ethoxalylation of llfi-hydroxy testosterone in the2-position by reaction with ethyl oxalate in a tertiary alkanol such ast-butanol in the presence of an alkali metal alkanolate, such as sodiummethylate, at room temperature to form 2 ethoxalyl-A androstene1113,1713 diol-3-one, reacting said product in an inert organic solvent,such as acetone, with methyl iodide in the presence of an alkali metalcarbonate, such as potassium carbonate at reflux temperatures to form2-methyl-2-ethoxalyl-n -androstene-115,175- diol-3-one, deacylating thelatter compound by reaction at about room temperature under anhydrousconditions with an alkali metal alkanolate dissolved in said alkanol,preferably with sodium ethylate in ethanol to form Zen-methyl-M-androstene-l15,17fi-diol-3-one, forming the 17-acetate of saidcompound by reaction with an acetylating agent, such as with aceticanhydride in pyridine at elevated temperatures up to the boiling point,dehydrogenating the said l7-acetate with selenium dioxide in thepresence of an inert solvent such as t-butanol at reflux temperatures toform the 17-acetate of Z-methyl-d -androstadiene- 116,17fi-dio1-3-one,saponifying the latter IT-acetate with an alkali metal hydroxide, suchas potassium hydroxide in methanol, at about room temperature, to formthe free aeeaaea 2 methyl-A -androstadiene-115,17B-diol-3-one, reactingdione, reacting the said dione in an inert organic solvent, preferably ahydrocarbon solvent such as toluene, with aluminum isopropylate in amixture of cyclohexanone and toluene to form Z-methyl-A-androstadiene-11,8-ol-3,17- dione, reacting the said dione in an inertorganic solvent, such as dioxane, with acetylene in the presence of analkali metal tertiary alkanolate, such as potassium tamylate, to formthe final product, Z-methyl-lh-ethynyl- A-androstadiene11/3,'l7B-diol-3-one.

While the above techniques are preferred, equivalent steps may be used.For example, the dehydrogenation of the l7-acetate ofZa-methyl-M-androstene-l15,17 8-di0l-3- one may be accomplished byfermentation with microorganisms such as Corynebacteriam simplex and theOppenauer reaction may be effected with any aluminum lower aikanolate.The saponification of the 17-acetate may be effected with other alkalineagents such as alkali metal or alkaline earth metal lower aleoholates.The ethynylation can be eflected with different solvents and in thepresence of other alkali metal tertiary alkanolates such as potassiumt-butylate. The ethynylation may also be eflected by producing theorganomagnesium derivatives of the ketone in the 17-position.

In the following examples there are described several embodiments toillustrate the invention. However, it should be understood that theinvention is not intended to be limited to the specific embodiments.

EXAMPLE Preparation of Z-Methyl-I7a-Ethynyl-A -Androstadiene-11B,17,B-Di0l-3-0ne (IX) Step A: Preparation of Z-ethxalyl-A-andr0stene- 1. ;8,17;3-di0l-3-0ne (II).Under mechanical agitation andin the absence of moisture, 25 gm. of 11fi-hydroxy testosterone and 400cc. of t-butanol were placed in a flask.

To this suspension 125 cc. of a methanol solution containing 12% ofsodium methylate were added over a period of around minutes under anatmosphere of nitrogen while agitating. Then, over a period of 15minutes, a solution of 28 cc. of ethyl oxalate in 100 cc. of t-butanolwas introduced. The reaction mixture was allowed to remain underagitation and under an atmosphere of nitrogen at room temperature. Atthe end of 18 hours the 2-ethoxalyl-A -androstene-113,17,8-diol-3- onewas separated in the form of its enolate with sodium, washed withmethylene chloride and dried under vacuum. This enolate was dissolved inwater, treated with 3 N hydrochloric acid, extracted by ethyl acetate.The extracts were combined and evaporated to dryness to give 32.3 gm. ofthe desired 2 ethoxalyl A androstene- 115,17B-di0l-3-one (II), a yieldof 97.5%.

Step B: Preparation ofZ-mcthyl-2-etlzoxalyl-M-androstene-I15,17,8-di0l-3-0ne (III).-Undermechanical agitation and in the absence of moisture, the followingmixture was introduced into a flask:

32.3 gm. of compound II (Z-ethoxalyl-A -androstene-11,8,17fi-diol-3-one) 740 cc. of acetone 130 cc. of methyl iodide 50 gm.of pulverized anhydrous potassium carbonate The reaction mixture washeated at reflux with agitation for 48 hours. The mixture was thenfiltered to eliminate the mineral salts and the precipitate was washedwith hot acetone. The filtrate was united with the acetone of thewashing step and evaporated under vacuum. The evaporation residue wastaken up in water and extracted by ethyl acetate. The extracts werewashed with a solu tion of 1% sodium hydroxide, then with a dilutesolution of sodium chloride and finally, with water, dried andevaporated under vacuum. 27.5 gm. or 80% of Z-methyl- 2-ethoxalyl-A-androstene-11,8,175-diol-3-one (III) were obtained.

Step C: Preparation 0 Za-methyl-M-androstene 115,]7fi-diol-3-0ne(IV).27.5 gm. of 2-methyl-2-ethoxalyl-d -androstene-l15,17,8-diol-3-one(III) were dissolved in 220 cc. of absolute ethanol by warming slightly.Then the solution obtained was allowed to come to room temperature.Under an atmosphere of nitrogen, 260 cc. of a solution of 3% of sodiumethylate in ethanol were introduced and the mixture was allowed toremain at room temperature in a dark place for 48 hours. The reactionmixture was then poured into 5 liters of a mixture of ice and water..fter saturating with sodium chloride, the product was extracted byethyl acetate. The extracts were washed with a 2% sodium hydroxidesolution, then with a dilute sodium chloride solution, and finally withwater, dried over magnesium sulfate, filtered and evaporated. 19 gm. or73% of 2a-methyl-A -androstenel1p,17p-diol-3-one (IV) were obtained.

Step D: Preparation of the 7-acezate of 2amethyl-M-androstene-JIBJ7,8-a'i0l-3-0n'e (V) .The following mixture Was placed in a flask in theabsence of moisture:

19 gm. of compound IV (2 x-methyl-A -androstene.

11fl,17,3-diol-3-one) cc. of anhydrous pyridine 40 cc. of acetic acidanhydride.

The temperature was raised slowly during a period of one hour to C., andthe reaction mixture was allowed to remain overnight at roomtemperature. The reaction mixture was then poured into 2.4 liters of amixture of ice and water and extracted with ethyl acetate. The extractswere combined, washed by dilute hydrochloric acid, then by a sodiumhydroxide solution, then by water, dried, and evaporated under vacuum.The residue was purified by trituration with isopropyl ether, then bymethylene chloride and recrystallized from absolute methanol. Thepurification can also be effected by chromatography on silicagel andeluting with methylene chloride containing 7% of acetone. 6.0 gm. of the17-acetate of 2a-methyl- A -androstene-11fi,17fl-diol-3-one (V) wereobtained, being a yield of 21% with reference to the starting compoundI. Product V had a melting point of 165 C. and a specific rotation [a]=|-156 (c.=1% in chloroform).

Analysis.-C H O molecular weight=360.48: Calculated: C, 73.30%; H,8.95%; O, 17.75%. Found: C, 73.2%; H, 8.9%; O, 17.5%.

Step E: Preparation of the 17-acetate of 2-methyl-Aandrostadiene-I1,6,17fl-di0l-3-0ne (Vl).-In a flask having a refluxcondenser and a nitrogen source there was placed:

1.05 gm. of the 17-acetate of 2a-methyl-A -androstene-11,8,17e-diol-3-one 56 cc. of t-butanol 1.1 cc. of acetic acid 700 mg.of pulverized selenium dioxide The mixture was heated to reflux undernitrogen for a period of hours, adding a supplemental 500 mg. ofselenium dioxide after 48 hours of heating, then mg. of selenium dioxideafter 72 hours. The reaction mixture was then cooled to roomtemperature, 40 cc. of ethyl acetate containing animal carbon black wereadded and the mixture filtered. The filtrate was evaporated under vacuumand the residue was taken up in ethyl acetate. The ethyl acetate extractwas Washed with a solution of sodium hydroxide, then with water, driedand evaporated under vacuum. The product was purified by chromatographyand recrystallized in ethanol. 560 mg. of the 17-acetate of 2-methyl-A-androstadiene-115,17,6- diol-3-one (VI), a yield of 57%, were obtained.Product VI had a melting point of 184-185 C. and a specific rotation [a]=+44 (c.=l% chloroform).

Analysis.-C H O molecular weight'=35 8.4 6: Calculated: C, 73.71%; H,8.44%; C, 17.85%. 73.6%; H, 8.4%; C, 18.1%.

Step F: Preparation of Z-methyl-A -androstadiene- 11,8,17fi-di0l-3-0ne(VII).--550 mg. of the 17-acetate of 2-methyl-A-androstadiene-11/3,17;3-diol-3-one (VI). were dissolved by slightheating in 12 cc. of methanol. The solution was allowed to return toroom temperature and 2.8 cc. of a potassium hydroxide solution inmethanol were added under nitrogen. The reaction mixture Was allowed tostand overnight at room temperature. The mixture Was then poured into 60cc. of water and ice. The gel formed was extracted by ethyl acetate andthe extracts were combined, washed and evaporated under vacuum. The2-methyl-A -androstadiene-l1 5,173- diol-3-one (VII) was recrystallizedin aqueous isopropanol, then in benzene. The yield was 70%. The productVII had a melting point of 261 C. and a specific rotation [a] =+44(c.=l% in dioxane).

Analysis.-C H O molecular weight=316.42: Calculated: C, 75.91%; H,8.92%. Found: C, 76.1%; H, 8.9%.

Step G: Preparation of 2-methyl-A -andr0stadiene- 11t3-0l-3J7-dz'one(VIII).The following mixture was placed in a flask in the absence ofmoisture:

540 mg. of 2-metl1y1-A -androstadiene-115,1713-dio1-3- one (VII) 75 cc.of anhydrous toluene.

Found: C,

The mixture was heated to the boiling point in order to dissolve the2-methyl-A -androstadiene-11,3,17p-diol- 3-one and 30 cc. of toluenewere distilled ofif in order to eliminate all traces of moisture.

There was then added through a dropping funnel, and without interruptionof the boiling, a solution of:

185 mg. of aluminum isopropylate 19 cc. of anhydrous toluene 3.1 cc. ofcyclohexanone.

The addition was effected over a period of about 50 minutes withsimultaneous distillation of 30 cc. of solvent. cc. of toluene were thenadded over the course of about 60 minutes while distilling to replacesolvent lost during distillation. The reaction mixture was cooled toroom temperature. 30 cc. of water were added and the mixture decanted.The organic phase was washed with a solution of 1% sulfuric acid, thenwith water, finally with a normal sodium hydroxide solution and againwith water. The organic phase was dried and evaporated under vacuum.Z-methyl A -androstadiene 11,8-ol-3,17- dione (VIII) was vacuum filteredand washed with petroleum ether, then recrystallized from benzene. Theyield was of the order of 70%. Product VIII had a melting point of228-229 C. and a specific rotation [oz] =-|ll0 (c.=1% in dioxane).

Analysis.C H O molecular weight=314.41: Ca1- culated: C, 76.39%; H,8.35%. Found: C, 76.3%; H, 8.5%.

Step H: Preparation of Z-methyl-I7a-ethynyl-Aandrostadiene-I15,17,8-di0l-3-0ne (IX) .-The following mixture wasplaced in a flask under mechanical agitation and in the absence ofmoisture:

8 cc. of anhydrous t-amyl alcohol 600 mg. of potassium The mixture washeated in an oil bath to slow reflux with agitation for an hour untilsolution of the potassium was complete. The flask was then cooled toroom temperature, 2 cc. of anhydrous benzene added, and for 2 hours acurrent of purified acetylene was passed in under agitation. A solutionof 375 mg. of Z-methyI-A androstadiene-l1,8-ol-3,17-dione in 5 cc. ofdry dioxane was then added and the introduction of acetylene continued,under violent agitation and at room temperature for 2 hours. Thereaction mixture was then cooled with the aid of an ice bath and 2.5 cc.of 50% acetic acid was added in small portions.

The 2 methyl-17a-ethynyl-A -androstadiene-116,175- diol-3-one wasextracted with chloroform. The extracts were combined, washed withwater, then with a 1% sodium carbonate solution and again with water,then dried over sodium sulfate and evaporated to dryness. The productobtained was recrystallized in a mixture of methylene chloride andmethyl acetate. The yield was 64%. The product had a melting point of249250 C. and a specific rotation 0: 20 (0.: 1% in momma-1333 32 55Analysis.--C H O molecular weight=340.44: Calculated: C, 77.61%; H,8.29%; C, 14.10%. Found: C, 77.7%; H, 8.4%; C, 14.3%.

Various modifications of the process and the products of the presentinvention may be made without departing from the spirit or scopethereof, and it is to he understood that the invention is limited onlyas defined in the appended claim.

We claim:

A compound having the formula pooe a on References Cited in the file ofthis patent UNITED STATES PATENTS 2,816,121 Gould et a1 Dec. 10, 19572,883,401 Babcock et a1 Apr. 21, 1959 2,900,398 Wettstein et a1 Aug. 18,1959 2,902,410 Wcintraub et al Sept. 1, 1959 2,906,759 Muller et a1Sept. 29, 1959 OTHER REFERENCES Velluz et al., Journ. Am. Chem. Soc.,April 1958, page 2026.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3 068252 December 11, 1962 Gerard Nomine et al0 It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected belo' Column 3 line 2for 'di0ne,, reacting the said dione in an inert read said free compoundin an anhydrous Signed and sealed this 25th day of June 1963a (SEAL)Attest:

ERNEST w. SWIDER DAVID LADD Attesting Officer Commissioner of Patents

